Impact of Acute Beta-Blocker Therapy for Patients with Non–ST-Segment Elevation Myocardial Infarction
Article Outline
Abstract
Purpose
Early use of beta-blockers is a quality indicator for the treatment of patients with non–ST-segment elevation myocardial infarction (NSTEMI), despite limited data from randomized clinical trials in this population. We sought to determine the impact of acute beta-blocker therapy on outcomes in patients with NSTEMI.
Subjects and Methods
We examined acute (<24 hours) beta-blocker use in 72,054 patients with NSTEMI from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) initiative at 509 US hospitals from 2001-2004. We analyzed patient and provider factors associated with beta-blocker use and the impact of beta-blocker therapy on unadjusted, risk-adjusted, and propensity matched outcomes in the overall sample and among selected high-risk subgroups.
Results
A total of 82.5% of patients without documented contraindications received acute beta-blocker therapy. Factors strongly associated with acute beta-blocker use included prior beta-blocker use, higher presenting systolic blood pressure, lower heart rate, lack of signs of heart failure, and cardiology care. Acute beta-blocker use was associated with lower in-hospital mortality (unadjusted 3.9% vs 6.9%, P <.001, adjusted odds ratio 0.66, 95% confidence interval 0.60-0.72), lower adjusted mortality among most of 6 subgroups determined by propensity to receive acute beta-blockers, and lower adjusted mortality in patients with and without signs of heart failure and in those <80 years and those ≥80 years old.
Conclusions
The majority of NSTEMI patients receive acute beta-blocker therapy. Certain patient subgroups remain undertreated. Because treatment with acute beta-blockers was associated with improved clinical outcomes in nearly all patient subgroups assessed, broader use in patients with NSTEMI appears warranted.
Keywords: Acute coronary syndromes, Beta blockers, Guidelines, Patient care
Medications that inhibit the β-adrenergic receptor have become widely accepted therapy for the management of patients with acute myocardial infarction and congestive heart failure. Randomized clinical trials performed before the reperfusion era for acute ST-segment elevation myocardial infarction demonstrated that beta-blockers improved early clinical outcomes.1, 2 A subsequent trial in patients with non–ST-segment myocardial infarction treated with fibrinolytics demonstrated that immediate beta-blocker use was associated with a lower incidence of recurrent ischemic events compared with delayed use.3 A more contemporary trial demonstrated that beta-blockers significantly reduce mortality and other adverse clinical outcomes in patients with left ventricular systolic dysfunction within 3-21 days of an acute myocardial infarction.4 Despite the broad benefits demonstrated across these studies, the recently completed Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2) demonstrated an early hazard and no mortality benefit when beta-blockers were administered within 24 hours of acute ST-segment elevation myocardial infarction.5
The updated American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with unstable angina and non–ST-segment myocardial infarction designate acute (<24 hours) use of beta-blockers as a class I recommendation. This is largely based on extrapolation from earlier beta-blocker studies that primarily enrolled patients with ST-segment elevation myocardial infarction, because few randomized trials of beta-blocker use for acute myocardial infarction have included patients with non–ST-segment elevation myocardial infarction.1, 2, 3, 4, 5, 6, 7 However, given the concerns raised by the findings of the COMMIT/CCS-2 trial about the early use of beta-blockers for acute myocardial infarction, we evaluated the use of acute beta-blockers for patients with non–ST-segment elevation myocardial infarction. Using data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Initiative, we sought to: describe contemporary patterns of acute use of beta-blockers in patients with non–ST-segment elevation myocardial infarction; determine patient, provider, and hospital factors associated with acute beta-blocker use; and determine the impact of acute beta-blocker use on clinical outcomes in the overall sample, among propensity groups, and among specific high-risk subgroups.
Methods
Patients meeting inclusion criteria for CRUSADE were identified locally by each site. Data collected included patient and hospital characteristics, use of acute medications (within 24 hours of presentation), medication contraindications, use and timing of invasive cardiac procedures, laboratory results, in-hospital outcomes, and discharge therapies and interventions.
Inclusion Criteria and Analysis Population
For inclusion in CRUSADE, patients must present to a participating institution with acute ischemic symptoms lasting ≥10 minutes in the preceding 24 hours, and have at least one of the following high-risk features: ST-segment depression ≥0.5 mm, transient ST-segment elevation 0.5-1.0 mm (lasting for <10 minutes), or positive cardiac markers (elevated troponin I or T or creatine kinase-MB greater than the upper limit of normal for the local laboratory assay). Patients transferring into a participating hospital
>24 hours after their last ischemic episode are not eligible for inclusion.
Of 115,950 patients included in CRUSADE between 2001 and 2004 at 509 US hospitals, the following were excluded from this analysis: 35,399 who transferred into or out of a participating hospital, 13,104 without positive cardiac markers, 1019 who did not have acute medications recorded, 209 who had incomplete information on acute beta-blocker use, and 7269 with listed contraindications to beta-blockers (bradycardia, >1st degree atrioventricular block, cardiogenic shock, hypotension, and chronic obstructive pulmonary disease or asthma). The remaining analysis population included 72,054 patients.
Clinical Endpoint Definitions
Clinical endpoints included all-cause mortality during the index hospitalization, post-admission infarction, in-hospital heart failure, and cardiogenic shock. Post-admission infarction was defined as patients who:×upper limit of normal (if preprocedural biomarkers were less than the upper limit of normal); or×upper limit of normal or develop new Q waves on ECG.
In-hospital heart failure was defined as signs, symptoms, and radiographic findings of heart failure that began after the initial history and physical examination or heart failure that recurred after initial signs of heart failure at presentation resolved. Cardiogenic shock was defined as persistent hypotension (systolic blood pressure <90 mm Hg) with signs of end-organ dysfunction such as oliguria, altered mental status, or poor peripheral perfusion. Nonfatal endpoints were reported by sites and were not centrally adjudicated.
Statistical Methods
For the descriptive analysis, patient baseline demographics, clinical characteristics, care patterns, and in-hospital outcomes were compared between patients who received beta-blockers versus those who did not. Medians and 25th and 75th percentiles were reported for continuous variables, and percentages were reported for categorical variables. The Wilcoxon test for continuous variables and the chi-squared test for categorical variables were used to test for differences.
We analyzed variables associated with acute use of beta-blockers using a logistic generalized estimating equations method.8 The generalized estimating equation method is used to adjust for correlations among clustered responses (ie, within hospital correlations for responses) where patients at the same hospital were more likely to have similar responses relative to patients in other hospitals. Variables in the model included patient demographics, presentation factors including prior use of beta-blockers, medical history, and certain hospital characteristics. Heart rate and age were entered into the model as continuous variables with linear splines to account for variations in the effect of the variable on beta-blocker use within different ranges of the continuous variables. Univariate analyses were then conducted to determine which of these factors could be expected to have an independent effect on beta-blocker use. All variables were then tested in multivariable analyses and results were evaluated in a stepwise fashion, sequentially eliminating nonsignificant variables considered clinically unimportant by the investigators and retaining significant variables considered to be of explanatory importance.
Finally, the association between acute beta-blocker therapy and in-hospital clinical outcomes also was assessed using the logistic generalized estimating equation method. Results were analyzed in 3 ways—overall, within high-risk subgroups, and within 6 strata of patients determined by the propensity to receive acute beta-blockers. The models used to determine adjusted clinical outcomes included patient demographics (age, sex, race), presenting characteristics (congestive heart failure, positive cardiac markers, systolic blood pressure, heart rate), medical history (family history, dyslipidemia, hypertension, renal insufficiency, prior myocardial infarction, prior coronary artery bypass grafting, prior percutaneous coronary intervention, prior stroke, prior congestive heart failure, current smoking, diabetes), and hospital characteristics (bed size, region, capabilities for invasive cardiac procedures and academic, teaching status).
A P value <.05 was considered statistically significant for all tests. All statistical analyses were performed using SAS software (version 8.2, SAS Institute, Cary, NC).
Results
A total of 82.5% of patients received acute beta-blockers. Patients who received acute beta-blockers were younger, more commonly male, had prior myocardial infarction, were more commonly taking prior beta-blockers, were cared for by cardiologists at academic hospitals, and less commonly had prior or current heart failure (Table 1). The independent factors associated with acute beta-blocker use are listed in Table 2.
Table 1. Patient and Hospital Characteristics by Acute Beta-Blocker Use
| Patient Characteristics | No Acute Beta-Blockers (n=12,612) | Acute Beta-Blockers (n=59,442) | P Value |
|---|---|---|---|
| Demographics | |||
| Age (years)⁎ | 71(58,80) | 69(57,79) | <.001 |
| Women (%) | 42.5 | 40.1 | <.001 |
| White (%) | 79.1 | 78.9 | .12 |
| Body mass index⁎ | 27.3(23.7,31.5) | 27.6(24.3,31.9) | <.001 |
| Medical history | |||
| Hypertension (%) | 66.5 | 71.5 | <.001 |
| Diabetes mellitus (%) | 33.8 | 33.7 | .95 |
| Current smoking (%) | 24.7 | 25.5 | .10 |
| Hyperlipidemia (%) | 41.0 | 48.8 | <.001 |
| Family history of coronary artery disease (%) | 32.4 | 34.4 | <.001 |
| Renal insufficiency (%)† | 14.6 | 15.1 | .022 |
| Prior stroke (%) | 12.0 | 11.3 | .024 |
| Prior myocardial infarction (%) | 27.8 | 31.8 | <.001 |
| Prior congestive heart failure (%) | 22.3 | 19.4 | <.001 |
| Prior percutaneous coronary intervention (%) | 19.3 | 21.3 | <.001 |
| Prior coronary artery bypass grafting (%) | 18.8 | 21.1 | <.001 |
| Presenting characteristics | |||
| ST depression (%) | 28.7 | 32.3 | <.001 |
| Transient ST-elevation (%) | 6.5 | 5.9 | <.001 |
| Signs of CHF (%) | 28.3 | 24.0 | <.001 |
| Systolic blood pressure (mm Hg)⁎ | 141(120,161) | 147(128,168) | <.001 |
| Heart rate (beats per minute)⁎ | 84(70,100) | 84(72,100) | .003 |
| Other features | |||
| Cardiology service (%)‡ | 48.4 | 53.7 | <.001 |
| Academic hospital (%)§ | 25.7 | 30.5 | <.001 |
| Prior beta-blocker use (%) | 21.0 | 44.6 | <.001 |
| Insurance status (%) | <.001 | ||
| HMO/Private | 41.3 | 44.7 | |
| Medicare | 44.1 | 41.3 | |
| Medicaid | 7.9 | 6.4 |
⁎Presented as median (25th, 75th percentile). |
†Creatinine >2.0 mg/dL, calculated creatinine clearance <30 mL/min, or need for chronic renal dialysis. |
‡Admission to a cardiology inpatient service. |
§Member of the Council of Teaching Hospitals. |
Table 2. Factors Associated with Acute Beta-Blocker Use
| Variable | χ2 | Adjusted OR | 95% CI |
|---|---|---|---|
| Prior beta-blocker use | 927 | 3.36 | 3.11-3.64 |
| SBP (per 10 mm Hg increase) | 241 | 1.06 | 1.05-1.06 |
| Signs of congestive heart failure | 112 | 0.76 | 0.72-0.80 |
| Heart rate⁎ | 108 | ||
| Heart rate <60 beats per minute | 1.018 | 1.011-1.025 | |
| Heart rate 60 to 100 beats per minute | 1.010 | 1.008-1.012 | |
| Heart rate >100 beats per minute | 0.997 | 0.996-0.999 | |
| Prior congestive heart failure | 75 | 0.78 | 0.73-0.82 |
| Cardiology inpatient service | 46 | 1.25 | 1.17-1.33 |
| Prior PCI | 45 | 0.81 | 0.77-0.87 |
| Insurance coverage | 30 | ||
| Medicare† | 0.96 | 0.91-1.01 | |
| Medicaid† | 0.78 | 0.72-0.86 | |
| Self-insurance† | 1.08 | 0.98-1.19 | |
| Age⁎ | 30 | ||
| Age <55 years | 1.002 | 0.995-1.009 | |
| Age 55-64 years | 0.990 | 0.980-0.999 | |
| Age 65-74 years | 0.989 | 0.980-0.997 | |
| Age 75-84 years | 1.001 | 0.992-1.009 | |
| Age ≥85 years | 1.003 | 0.991-1.015 | |
| ECG findings | 23 | ||
| ST depression‡ | 1.12 | 1.07-1.17 | |
| Transient ST elevation‡ | 1.15 | 1.03-1.28 | |
| ST depression+Transient ST elevation‡ | 1.23 | 1.03-1.47 | |
| Academic hospital§ | 8 | 1.30 | 1.09-1.55 |
| Male sex | 8 | 1.06 | 1.02-1.11 |
| Hyperlipidemia | 7 | 1.07 | 1.02-1.12 |
| Family history of CAD | 4 | 1.05 | 1.00-1.11 |
| Renal insufficiency∥ | 4 | 0.95 | 0.89-1.00 |
⁎Heart rate and age entered into model as continuous variables with no reference group, but linear splines were performed for each variable to account for variations in the slope of the distribution of the variables within each listed segment. χ2 values represent strength of the association of the overall variable. |
†Compared with health maintenance organization/private insurance. |
‡Compared with neither ST depression nor transient ST elevation. |
§Member of the Council of Teaching Hospitals. |
∥Creatinine >2.0 mg/dL, calculated creatinine clearance <30 mL/min, or need for chronic renal dialysis. |
Patients treated with acute beta-blockers more commonly received other acute medical therapies and more commonly underwent invasive cardiac procedures (Table 3).
Table 3. Concomitant Acute (<24 h) Medications and Invasive Procedures by Acute Beta-Blocker Use⁎
| Variable | No Acute Beta-Blockers (n=12,612) | Acute Beta-Blockers (n=59,442) |
|---|---|---|
| Aspirin | 84.3% | 94.7% |
| Clopidogrel | 32.1% | 47.5% |
| Heparin (any) | 73.1% | 86.7% |
| Glycoprotein IIb/IIIa inhibitor | 25.6% | 40.8% |
| Cardiac catheterization | 62.2% | 75.2% |
| Cath ≤24 h of arrival | 26.2% | 34.5% |
| Arrival to cath (h)† | 27.3(12.8,53.9) | 25.2(11.9,49.4) |
| PCI | 36.5% | 45.5% |
| PCI ≤24 h of arrival | 16.5% | 22.6% |
| Arrival to PCI (h)† | 25.6(8.8,51.2) | 23.0(7.5,47.3) |
| Coronary artery bypass grafting | 11.4% | 13.3% |
⁎Only subjects without contraindications for each medication are included. |
†Values are median (25th, 75th percentile). |
In the overall sample, patients treated with acute beta-blockers had lower rates of unadjusted and adjusted in-hospital mortality (3.9% vs 6.9%, adjusted odds ratio [AOR] 0.66, 95% confidence interval [CI], 0.60-0.72), reinfarction (3.0% vs 3.6%, AOR 0.80, 95% CI, 0.72-0.89), and cardiogenic shock (2.1% vs 3.2%, AOR 0.76, 95% CI, 0.67-0.87) compared with patients not treated with acute beta-blockers. No difference in the unadjusted or adjusted risk of congestive heart failure was demonstrated (9.0% vs 9.7%, AOR 1.00, 95% CI, 0.92-1.08). Similar findings were noted in subgroups such as those with and without signs of congestive heart failure on presentation and those <80 years of age and those ≥80 years of age (Figure 1).
Figure 1.
Adjusted risk of in-hospital clinical outcomes by acute beta-blocker use. Patients in the congestive heart failure (CHF) group had signs of CHF upon hospital presentation.
Acute beta-blocker use was associated with a significantly lower risk of adjusted mortality across groups of patients categorized based upon the propensity to receive acute beta-blockers, except for the group with the greatest propensity to receive acute beta-blockers where a nonsignificant reduction in adjusted mortality was demonstrated (Figure 2).
Figure 2.
Adjusted risk of in-hospital mortality among propensity groups. Patients were categorized into 6 equal groups based upon the propensity to receive acute beta-blockers ranging from those with the lowest propensity (Group 1, 66.5%) to those with the highest propensity (Group 6, 92.4%).
Discussion
Our results show that more than 80% of eligible patients with non–ST-segment elevation myocardial infarction were treated with acute beta-blockers within 24 hours of hospital presentation. Patients who received acute beta-blockers were more likely to have been receiving beta-blockers prior to hospitalization, have stable hemodynamic features, and receive care on a cardiology inpatient service. Use of acute beta-blockers was associated with a lower adjusted risk of adverse outcomes across different patient subgroups and propensity groups.
Recent clinical trials include the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial that evaluated the use of oral beta-blockers within 3-21 days after acute myocardial infarction (both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction) complicated by left ventricular systolic dysfunction and demonstrated a significant reduction in long-term (>1 year) mortality, reinfarction, and arrhythmias.4, 9, 10, 11, 12 In contrast, the COMMIT/CCS-2 trial demonstrated an early hazard (increased risk of hypotension, bradycardia, CHF, and cardiogenic shock) coupled with early benefits (decreased risk of ventricular fibrillation and reinfarction) with immediate use of beta-blockers for patients with acute myocardial infarction (93% had ST-segment elevation myocardial infarction).8 However, follow-up in the COMMIT/CCS-2 trial was limited to the hospitalization period, which was no longer than 28 days; close to half of the patients did not receive reperfusion therapy, use of catheterization and revascularization procedures was not permitted, and no mortality benefit was demonstrated.5
In contrast to randomized clinical trials that often include patients with both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction, our patient population represents a true non–ST-segment elevation myocardial infarction cohort. In this analysis we have shown improved in-hospital outcomes with acute beta-blockers in a contemporary population of patients with non–ST-segment elevation myocardial infarction treated in routine practice who commonly received other evidence-based medications and underwent revascularization procedures. Although our results may be limited by the lack of follow-up after discharge, other observational studies have shown discharge use of beta-blockers in elderly patients with acute myocardial infarction (both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction) is associated with reduced mortality, even among those who underwent revascularization procedures.13, 14
Results from CRUSADE supplement evidence from randomized clinical trials by showing that acute beta-blockers are beneficial for patients with non–ST-segment elevation myocardial infarction and are consistent with other registry data. The National Cooperative Cardiovascular Project retrospectively evaluated the impact of beta-blocker prescribing at hospital discharge on long-term mortality among patients with acute myocardial infarctions. Among these Medicare patients, beta-blocker prescribing at discharge was associated with a 14% decrease in mortality at 1 year.13 Subgroup analysis of this population demonstrated a similar mortality benefit to beta-blocker use among patients with ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction at 2 years.15
Previous analyses that showed enhanced benefit with beta-blockers among high-risk subgroups of patients with acute myocardial infarction led us to evaluate the benefit of acute beta-blocker use in patient subpopulations, including the elderly and those with congestive heart failure on arrival.1, 2, 3, 4, 15 In CRUSADE, we found similar benefits with acute beta-blocker therapy in younger vs. older patients and for patients with and without signs of congestive heart failure on presentation. Our results are similar to those from other studies that found reduced long-term mortality with beta-blockers in the elderly and those with congestive heart failure or left ventricular systolic dysfunction, but we also have shown that older patients and those with congestive heart failure were less likely to receive acute beta-blockers.4, 14, 15 Clinicians may have concerns about using acute beta-blockers in these types of patients with acute myocardial infarction, given the increased risk of shock and hypotension seen with beta-blockers in prior trials, especially among patients with signs of congestive heart failure (who have high baseline risks of adverse outcomes) and very elderly patients (who were not commonly enrolled in randomized trials of acute beta-blockers).5, 16, 17 Although we acknowledge these concerns, our findings suggest that these high-risk patients benefit from acute beta-blocker use. However, it is important not to extrapolate these findings to patients with cardiogenic shock, as these patients were excluded from our analysis. In order to enhance patient care, further studies are needed to delineate factors limiting the use of beta-blockers in certain populations. Through this information, interventions can be designed to improve beta-blocker use in undertreated subgroups that may receive a greater relative benefit from this treatment.18
Significant knowledge deficits exist about the use of beta-blockers in patients with non–ST-segment elevation myocardial infarction. Most investigations have not evaluated only patients with non–ST-segment elevation myocardial infarction and, thus, the evidence for benefit in this population has been limited. Our results from over 72,000 patients with definite non–ST-segment elevation myocardial infarction prove the administration of beta-blockers in the first 24 hours is associated with mortality benefit at the time of hospital discharge. This information augments the results from the National Cooperative Cardiovascular Project showing that patients with non–ST-segment elevation myocardial infarction who are discharged on beta-blockers have a lower mortality rate at 2 years.15 Although registry data cannot take the place of a randomized clinical trial, it represents the best available information at this time. Coupling these results together, patients with non–ST-segment elevation myocardial infarction without contraindications should be treated acutely and over the long term with beta-blocker medications.
As an observational, retrospective analysis, certain limitations were present. First, hospitals included in CRUSADE were actively seeking to improve performance and may not be representative of all US hospitals. Second, although we excluded patients with contraindications to acute beta-blocker use, undocumented contraindications may explain the nonuse of acute beta-blockers in at least a portion of the 17.5% of patients who did not receive them, especially because these patients were more likely to have lower blood pressure and signs of congestive heart failure. Furthermore, because prior beta-blocker use was the factor most strongly associated with acute beta-blocker use, previous tolerance to beta-blockers may have driven the continued use of beta-blockers during the acute care period, rather than specific indications for beta-blocker use from the new, acute ischemic event that prompted hospitalization. Third, although we evaluated the impact of acute beta-blockers on adjusted clinical outcomes with multiple techniques, our results were likely influenced by unmeasured confounders. Fourth, we did not collect data on the dose, type, or method of administration (intravenous or oral) of acute beta-blockers and, thus, could not ascertain how these features influenced the results. Furthermore, data collection was limited to the in-hospital period, so we could not determine the long-term impact of acute beta-blocker use. Fifth, post-admission infarction was defined as any elevation in cardiac biomarkers after admission. This definition does not discriminate between those patients presenting with a myocardial infarction in evolution and those who had an event after arrival to the hospital. An additional limitation is the exclusion of transferred patients, which could reduce the generalizability of our findings. Finally, hospitals were encouraged to submit data on consecutive patients, but privacy regulations prevented verification of consecutive patient inclusion.
The majority of eligible patients with non–ST-segment elevation myocardial infarction in contemporary practice were treated with beta-blockers <24 hours from arrival. High-risk patients were less likely to receive this therapy even though the beneficial impact of beta-blockers was seen across patient subgroups and did not vary significantly by the propensity to receive beta-blockers. Although quality indicators for acute myocardial infarction (both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction) recommend beta-blockers within 24 hours, contraindications are not specified and the highest-risk patients with the greatest predicted benefit from beta-blockers may not be clearly targeted within these quality recommendations.19 Thus, further efforts are needed to reduce treatment gaps for the use of beta-blockers for acute myocardial infarction, and additional studies are needed to clarify the optimal timing for initiating beta-blocker therapy based upon patient risk factors and hemodynamic status.
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- Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005;45:525–530
- National use and effectiveness of β-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA. 1998;280:623–629
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- ACC/AHA clinical performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on performance measures (writing committee to develop performance measures on ST-elevation and non-ST-elevation myocardial infarction). Circulation. 2006;113:732–761
CRUSADE is funded by the Schering-Plough Corporation. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership provides additional funding support. Millennium Pharmaceuticals, Inc. also funded this work.
PII: S0002-9343(07)00413-5
doi:10.1016/j.amjmed.2007.04.016
© 2007 Elsevier Inc. All rights reserved.
